- Email: [email protected]
A New Twist on Tip Links
Neuron
Previews A New Twist on Tip Links Tobias F. Bartsch1,* and A.J. Hudspeth1 1Howard Hughes Medical Institute and Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.07.041
Auditory transduction is fast and sensitive owing to the direct detection of mechanical stimuli by hair cells, the sensory receptors of the internal ear. A study by Dionne et al. (2018) in this issue of Neuron suggests how signals propagate through tip links, the cadherin-based strands that gate mechanically sensitive channels. By transducing mechanical stimuli into electrical signals, hair cells undergird our auditory and vestibular senses. Each hair cell features a hair bundle, a cluster of stiff, actin-filled protrusions—the stereocilia—that are arranged in a staircase pattern. Sound waves excite vibrations in the inner ear that deflect a bundle back and forth. A whisper displaces the bundle by only a few hundred picometers, whereas the painful noise of a nearby jet engine causes bundle motion of hundreds of nanometers. Hair-bundle displacements are transduced into cellular depolarizations through a mechanical apparatus that underlies the high-frequency response of the auditory system (reviewed in Hudspeth, 2014). Each stereocilium is connected to its tallest neighbor by a filamentous tip link, a dimer of dimers of atypical cadherins whose lower third is formed by protocadherin 15 and whose top two-thirds consists of cadherin 23. The lower end of the tip link is thought to be coupled to one or two mechanically gated ion channels. Deflection of a hair bundle toward its tall edge increases the tension in each tip link, which in turn opens the channels, allows the flow of K+ and Ca2+ into the hair cell, and thus initiates electrical signaling to the brain. For a hair cell to be able to discriminate between different sound intensities, progressively greater deflections of a hair bundle must increase the channels’ open probability in a graded fashion. A continuous increase in channel open probability can be achieved by means of a ‘‘gating spring’’ that couples bundle displacement to the molecular gates of the ion channels (Corey and Hudspeth, 1983). Increases in stimulation are thought to augment gating-spring tension, biasing the channels to higher open
probabilities. Measurements of hairbundle mechanics indicate that a gating spring has a stiffness of 1–4 mN/m and can extend by about 100 nm (Sotomayor et al., 2005). The identity of the gating spring remains controversial, however: it might include the tip-link cadherins themselves, unidentified molecules lying in series with them, or some combination. To shed light on the nature of the gating spring, Marcos Sotomayor and associates determined the crystallographic structures of several short segments of the tip-link cadherins and assessed their mechanical properties in molecular dynamics simulations (Sotomayor et al., 2012; Araya-Secchi et al., 2016; Powers et al., 2017). The connection between protocadherin 15 and cadherin 23 was found to resemble a ‘‘handshake’’ between the two amino-terminal extracellular cadherin domains (EC1 and EC2) of the two proteins. In simulations, the handshake can resist high forces while stretching only by a few nanometers, indicating a very stiff structure (Sotomayor et al., 2012). A fragment of protocadherin 15 comprising EC3–EC5 was likewise predicted to be several orders of magnitude too stiff to contribute significantly to the elasticity of the gating spring (Powers et al., 2017). The sole compliant element identified so far is a flexure between EC9 and EC10, which in simulations straightens under physiological forces and elongates protocadherin 15 by 4 nm with a stiffness of 8 mN/m (Araya-Secchi et al., 2016). This effect alone, however, is far too small to account for the in vivo extensibility and elasticity of the gating spring. In this issue of Neuron, Dionne et al. (2018) investigate the structure of parallel protocadherin 15 dimers. The extracellular domain of protocadherin 15 consists
of a chain of 11 extracellular cadherin domains (Figure 1A) coupled to the membrane-proximal PICA domain. Biophysical analysis of overlapping fragments consisting of two, three, or four adjacent domains identifies two distinct dimerization sites: the first occurs within EC3; the second, at the other end of the protein, is part of the PICA domain. The positions of these sites make sense: the first occurs immediately adjacent to the handshake between protocadherin 15 and cadherin 23 and likely stabilizes that interaction; the second site prevents ‘‘split ends’’ at a tip link’s membrane insertion. A crystal structure of the EC1–EC3 homodimer offers insight into the first cis-dimerization interface, which comprises both the junction between EC2 and EC3 and a loop that extends from each monomer’s EC3 to embrace that of the other. The first two cadherin domains of each monomer protrude to form the sides of a binding pocket for the trans-dimerization handshake with cadherin 23. Dionne et al. (2018) find that the cis-dimerization interface is necessary for mechanotransduction; even though cadherins bearing interface-disrupting mutations localize properly to the stereociliary tips of murine hair cells, transduction is impaired. It is unclear whether the mutations hinder tip-link formation or yield links with deficient mechanical properties. How are the remaining domains from EC4 to PICA arrayed? Electron micrographs suggest a double-helical arrangement that encompasses about 2.5 complete turns along the tip link (Kachar et al., 2000). The new study supports this architecture by single-particle cryoelectron microscopy: three-dimensional reconstruction of the full extracellular domain of dimeric protocadherin 15
Neuron 99, August 8, 2018 ª 2018 Elsevier Inc. 423
Neuron
Previews A EC1 EC2 EC3
B
C
D
E
F
G
Cadherin 23 Handshake interaction cisdimerization
EC4 EC5 EC6 EC7 EC8 EC9 EC10 EC11 PICA
cisdimerization
Figure 1. Possible Mechanisms of Protocadherin 15 Elongation under Tension (A) Each protocadherin 15 monomer comprises 11 extracellular cadherin domains (EC1–EC11) and a protocadherin 15 interacting-channel associated (PICA) domain. EC1 and EC2 participate in the handshake linkage with a dimer of cadherin 23, of which only the two amino-terminal domains are shown. Protocadherin 15 dimerizes through intermolecular contacts at EC3 and in the PICA domain. Note that the two strands of the dimer cross at the scissors-like upper dimerization site. (B) An unloaded monomer is depicted schematically as a sequence of 11 extracellular cadherin domains, each a sandwich of seven b strands. In this and the subsequent panels, the PICA domain is not shown. (C) The application of tension (red arrow) might elongate individual domains if they were sufficiently compliant. (D) Force could extract some strands from an extracellular cadherin domain (left) or even unfold the domain entirely (right). (E) If there is a prominent kink between adjacent domains (left), tension could straighten that region (right). (F) If dimeric protocadherin 15 is helical (left), the application of force could untwist the structure (right) and elongate the tip link. (G) Because bombardment by water molecules should induce multiple bends in each monomer (left), tension could straighten the molecule by working against entropic elasticity.
shows a double-helical half-turn. The remainder of the tip link’s helix presumably consists of cadherin 23, which, though 2.5 times as long as protocadherin 15, must account for at least four times as many helical half-turns—a curious and unresolved discrepancy. How might the structures of tip-link cadherins, which consist primarily of strings of tightly folded b sandwiches (Figure 1B), contribute to the mechanical properties of the gating spring? A link might display significant elasticity owing to the extensibility of individual extracellular cadherin domains, the unfolding and refolding of individual domains, or the rearrangement of the domains relative to each other. Extracellular cadherin domains are likely too stiff to extend enough under physiological forces to contribute signifi424 Neuron 99, August 8, 2018
cantly to the elasticity of the gating spring (Figure 1C; Sotomayor et al., 2005). Whether any domains unfold and refold under relevant tensions remains to be determined (Figure 1D). When domains under tension are simulated for a few nanoseconds, unfolding does not occur unless unrealistically high forces are applied. However, because moleculardynamics simulations cannot access the timescales relevant to hearing, it is unclear whether unfolding would occur under physiological tension if the proteins were given enough time to surmount the energy barriers between folded and unfolded states. Gating springs are known to display viscoelasticity (Kozlov et al., 2012), which could signal energy losses as a result of unfolding and refolding parts of the tip-link cadherins under physiological forces.
Application of a force to the tip-link proteins might alter the arrangement of their cadherin domains. For example, straightening of the putative bend between EC9 and EC10 of protocadherin 15 could provide a small extension under relevant forces (Figure 1E). Because this flexure is absent in the cryo-electron microscopic class averages presented by Dionne et al. (2018), those authors suggest a different and novel way in which cadherin domains could be rearranged: the helix might unwind under tension, elongating the tip link and contributing compliance to the gating spring (Figure 1F). However, tip links imaged in situ (Kachar et al., 2000) evidently sustain considerable resting tension in the absence of a stimulus. They nonetheless show a helical structure similar to that of the dimeric protocadherin 15 imaged by Dionne et al. (2018) under force-free conditions. This observation suggests that, if the tip link unwinds at all, it does so only under relatively large forces. Additional mechanisms therefore seem necessary to explain the extensibility and stiffness of the gating spring. In particular, a possible entropic contribution to the tip link’s elasticity has largely been ignored. Electron microscopic and crystallographic structures portray the tip link and its constituent proteins as rigid objects that, like macroscopic structures, remain in a given conformation unless exposed to external forces. This impression is misleading. Surrounded by aqueous endolymph, a relaxed tip link is constantly bombarded by water clusters that bend it laterally. Such thermal forces ensure that the link undergoes continuous fluctuations in shape, spending most of its existence with random thermal bends and rarely assuming a straight configuration. To straighten the link by pulling out some of its thermal bends requires the application of an external force; the ensuing work is performed against the link’s entropic elasticity (Figure 1G). Because the mechanical properties of tip-link cadherins are unknown, it is uncertain to what extent entropic elasticity contributes to gating-spring stiffness. An important challenge for future research is to probe the mechanics of tip-link cadherins in single-molecule experiments in order to determine the relative importance of the possible modes of extensibility.
Neuron
Previews ACKNOWLEDGMENTS This work was partially supported by a Junior Fellow award from the Simons Foundation to T.F.B. A.J.H. is an Investigator of Howard Hughes Medical Institute.
Dionne, G., Qiu, X., Rapp, M., Liang, X., Zhao, B., Peng, G., Katsamba, P.S., Ahlsen, G., Rubinstein, R., Potter, C.S., et al. (2018). Mechanotransduction by PCDH15 relies on a novel cis-dimeric architecture. Neuron 99, this issue, 480–492.
REFERENCES
Hudspeth, A.J. (2014). Integrating the active process of hair cells with cochlear function. Nat. Rev. Neurosci. 15, 600–614.
Araya-Secchi, R., Neel, B.L., and Sotomayor, M. (2016). An elastic element in the protocadherin-15 tip link of the inner ear. Nat. Commun. 7, 13458.
Kachar, B., Parakkal, M., Kurc, M., Zhao, Y., and Gillespie, P.G. (2000). High-resolution structure of hair-cell tip links. Proc. Natl. Acad. Sci. USA 97, 13336–13341.
Corey, D.P., and Hudspeth, A.J. (1983). Kinetics of the receptor current in bullfrog saccular hair cells. J. Neurosci. 3, 962–976.
Kozlov, A.S., Andor-Ardo´, D., and Hudspeth, A.J. (2012). Anomalous Brownian motion discloses viscoelasticity in the ear’s mechanoelectrical-
transduction apparatus. Proc. Natl. Acad. Sci. USA 109, 2896–2901. Powers, R.E., Gaudet, R., and Sotomayor, M. (2017). A partial calcium-free linker confers flexibility to inner-ear protocadherin-15. Structure 25, 482–495. Sotomayor, M., Corey, D.P., and Schulten, K. (2005). In search of the hair-cell gating spring: elastic properties of ankyrin and cadherin repeats. Structure 13, 669–682. Sotomayor, M., Weihofen, W.A., Gaudet, R., and Corey, D.P. (2012). Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction. Nature 492, 128–132.
Hippocampal Mossy Cells Provide a Fate Switch for Adult Neural Stem Cells Vero´nica C. Piatti1 and Alejandro F. Schinder1,* 1Laboratorio de Plasticidad Neuronal, Fundacio ´ n Instituto Leloir–Instituto de Investigaciones Bioquı´micas de Buenos Aires–Consejo Nacional
de Investigaciones Cientı´ficas y Te´cnicas (CONICET), Av. Patricias Argentinas 435, Buenos Aires C1405BWE, Argentina *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.07.044
The pathways that convert neural stem cells (NSCs) into functional neurons in the adult hippocampus are tightly regulated. In this issue of Neuron, Yeh et al. (2018) demonstrate that the activity of dentate mossy cells determines the balance between quiescence and activation of NSCs. Neuronal plasticity is the ability of nervous system networks to adjust to the dynamic conditions in the environment. In most circuits, plasticity is expressed as changes in synaptic weight. In a few regions of the adult brain such as the dentate gyrus (DG) of the hippocampus, plasticity also includes neurogenesis: the generation of entire new sets of functional units, the dentate granule cells (GCs). Positive experiences such as enriched environment (EE), voluntary exercise, or spatial learning increase the rate of neurogenesis and accelerate neuronal integration in the existing circuits. In contrast, stress and several pathological conditions reduce this plasticity or render abnormal connectivity of new GCs. Interestingly, not only experience exerts an impact on neurogenesis; new GCs also modify behavior, contributing to cognitive flexibility and
mood regulation (Toda and Gage, 2017). It is thus crucial to understand the mechanisms that control the generation and integration of adult-born GCs. The process starts from quiescent radial neural stem cells (NSCs) that—upon activation—divide, produce amplifying progenitor cells and, finally, produce the daughter cells that may became neuroblasts that will mature and integrate during several weeks into local and long-range dentate circuits (Toda and Gage, 2017). Several steps in the neurogenic pathway from NSCs to the final stages of maturation are modulated in response to mood and cognitive demand. While the parameters that rule these forms of network homeostasis remain largely unknown, it is becoming clear that network activity plays a fundamental role. What cells are the main activity sensors?
The DG is a sparse network in which principal neurons, the GCs, are mostly silent due to a strong GABAergic tone (Piatti et al., 2013). In contrast, mossy cells (MCs), glutamatergic dentate interneurons, are very active and have been proposed as sentinels of the DG network (Scharfman, 2017). Their major inputs arise from GCs, local GABAergic interneurons of the hilus and back-projections from CA3 pyramidal cells. Their output covers a long range of targets. The associational pathway, where axons extend ipsilaterally, covers about 60% of the longitudinal DG axis. The commissural pathway projects to the contralateral DG (Larimer and Strowbridge, 2008; Scharfman, 2017). Therefore, MCs have the capacity to integrate and adjust activity within the DG through excitatory feedback loops connecting GCs and local
Neuron 99, August 8, 2018 ª 2018 Elsevier Inc. 425
Previews A New Twist on Tip Links Tobias F. Bartsch1,* and A.J. Hudspeth1 1Howard Hughes Medical Institute and Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.07.041
Auditory transduction is fast and sensitive owing to the direct detection of mechanical stimuli by hair cells, the sensory receptors of the internal ear. A study by Dionne et al. (2018) in this issue of Neuron suggests how signals propagate through tip links, the cadherin-based strands that gate mechanically sensitive channels. By transducing mechanical stimuli into electrical signals, hair cells undergird our auditory and vestibular senses. Each hair cell features a hair bundle, a cluster of stiff, actin-filled protrusions—the stereocilia—that are arranged in a staircase pattern. Sound waves excite vibrations in the inner ear that deflect a bundle back and forth. A whisper displaces the bundle by only a few hundred picometers, whereas the painful noise of a nearby jet engine causes bundle motion of hundreds of nanometers. Hair-bundle displacements are transduced into cellular depolarizations through a mechanical apparatus that underlies the high-frequency response of the auditory system (reviewed in Hudspeth, 2014). Each stereocilium is connected to its tallest neighbor by a filamentous tip link, a dimer of dimers of atypical cadherins whose lower third is formed by protocadherin 15 and whose top two-thirds consists of cadherin 23. The lower end of the tip link is thought to be coupled to one or two mechanically gated ion channels. Deflection of a hair bundle toward its tall edge increases the tension in each tip link, which in turn opens the channels, allows the flow of K+ and Ca2+ into the hair cell, and thus initiates electrical signaling to the brain. For a hair cell to be able to discriminate between different sound intensities, progressively greater deflections of a hair bundle must increase the channels’ open probability in a graded fashion. A continuous increase in channel open probability can be achieved by means of a ‘‘gating spring’’ that couples bundle displacement to the molecular gates of the ion channels (Corey and Hudspeth, 1983). Increases in stimulation are thought to augment gating-spring tension, biasing the channels to higher open
probabilities. Measurements of hairbundle mechanics indicate that a gating spring has a stiffness of 1–4 mN/m and can extend by about 100 nm (Sotomayor et al., 2005). The identity of the gating spring remains controversial, however: it might include the tip-link cadherins themselves, unidentified molecules lying in series with them, or some combination. To shed light on the nature of the gating spring, Marcos Sotomayor and associates determined the crystallographic structures of several short segments of the tip-link cadherins and assessed their mechanical properties in molecular dynamics simulations (Sotomayor et al., 2012; Araya-Secchi et al., 2016; Powers et al., 2017). The connection between protocadherin 15 and cadherin 23 was found to resemble a ‘‘handshake’’ between the two amino-terminal extracellular cadherin domains (EC1 and EC2) of the two proteins. In simulations, the handshake can resist high forces while stretching only by a few nanometers, indicating a very stiff structure (Sotomayor et al., 2012). A fragment of protocadherin 15 comprising EC3–EC5 was likewise predicted to be several orders of magnitude too stiff to contribute significantly to the elasticity of the gating spring (Powers et al., 2017). The sole compliant element identified so far is a flexure between EC9 and EC10, which in simulations straightens under physiological forces and elongates protocadherin 15 by 4 nm with a stiffness of 8 mN/m (Araya-Secchi et al., 2016). This effect alone, however, is far too small to account for the in vivo extensibility and elasticity of the gating spring. In this issue of Neuron, Dionne et al. (2018) investigate the structure of parallel protocadherin 15 dimers. The extracellular domain of protocadherin 15 consists
of a chain of 11 extracellular cadherin domains (Figure 1A) coupled to the membrane-proximal PICA domain. Biophysical analysis of overlapping fragments consisting of two, three, or four adjacent domains identifies two distinct dimerization sites: the first occurs within EC3; the second, at the other end of the protein, is part of the PICA domain. The positions of these sites make sense: the first occurs immediately adjacent to the handshake between protocadherin 15 and cadherin 23 and likely stabilizes that interaction; the second site prevents ‘‘split ends’’ at a tip link’s membrane insertion. A crystal structure of the EC1–EC3 homodimer offers insight into the first cis-dimerization interface, which comprises both the junction between EC2 and EC3 and a loop that extends from each monomer’s EC3 to embrace that of the other. The first two cadherin domains of each monomer protrude to form the sides of a binding pocket for the trans-dimerization handshake with cadherin 23. Dionne et al. (2018) find that the cis-dimerization interface is necessary for mechanotransduction; even though cadherins bearing interface-disrupting mutations localize properly to the stereociliary tips of murine hair cells, transduction is impaired. It is unclear whether the mutations hinder tip-link formation or yield links with deficient mechanical properties. How are the remaining domains from EC4 to PICA arrayed? Electron micrographs suggest a double-helical arrangement that encompasses about 2.5 complete turns along the tip link (Kachar et al., 2000). The new study supports this architecture by single-particle cryoelectron microscopy: three-dimensional reconstruction of the full extracellular domain of dimeric protocadherin 15
Neuron 99, August 8, 2018 ª 2018 Elsevier Inc. 423
Neuron
Previews A EC1 EC2 EC3
B
C
D
E
F
G
Cadherin 23 Handshake interaction cisdimerization
EC4 EC5 EC6 EC7 EC8 EC9 EC10 EC11 PICA
cisdimerization
Figure 1. Possible Mechanisms of Protocadherin 15 Elongation under Tension (A) Each protocadherin 15 monomer comprises 11 extracellular cadherin domains (EC1–EC11) and a protocadherin 15 interacting-channel associated (PICA) domain. EC1 and EC2 participate in the handshake linkage with a dimer of cadherin 23, of which only the two amino-terminal domains are shown. Protocadherin 15 dimerizes through intermolecular contacts at EC3 and in the PICA domain. Note that the two strands of the dimer cross at the scissors-like upper dimerization site. (B) An unloaded monomer is depicted schematically as a sequence of 11 extracellular cadherin domains, each a sandwich of seven b strands. In this and the subsequent panels, the PICA domain is not shown. (C) The application of tension (red arrow) might elongate individual domains if they were sufficiently compliant. (D) Force could extract some strands from an extracellular cadherin domain (left) or even unfold the domain entirely (right). (E) If there is a prominent kink between adjacent domains (left), tension could straighten that region (right). (F) If dimeric protocadherin 15 is helical (left), the application of force could untwist the structure (right) and elongate the tip link. (G) Because bombardment by water molecules should induce multiple bends in each monomer (left), tension could straighten the molecule by working against entropic elasticity.
shows a double-helical half-turn. The remainder of the tip link’s helix presumably consists of cadherin 23, which, though 2.5 times as long as protocadherin 15, must account for at least four times as many helical half-turns—a curious and unresolved discrepancy. How might the structures of tip-link cadherins, which consist primarily of strings of tightly folded b sandwiches (Figure 1B), contribute to the mechanical properties of the gating spring? A link might display significant elasticity owing to the extensibility of individual extracellular cadherin domains, the unfolding and refolding of individual domains, or the rearrangement of the domains relative to each other. Extracellular cadherin domains are likely too stiff to extend enough under physiological forces to contribute signifi424 Neuron 99, August 8, 2018
cantly to the elasticity of the gating spring (Figure 1C; Sotomayor et al., 2005). Whether any domains unfold and refold under relevant tensions remains to be determined (Figure 1D). When domains under tension are simulated for a few nanoseconds, unfolding does not occur unless unrealistically high forces are applied. However, because moleculardynamics simulations cannot access the timescales relevant to hearing, it is unclear whether unfolding would occur under physiological tension if the proteins were given enough time to surmount the energy barriers between folded and unfolded states. Gating springs are known to display viscoelasticity (Kozlov et al., 2012), which could signal energy losses as a result of unfolding and refolding parts of the tip-link cadherins under physiological forces.
Application of a force to the tip-link proteins might alter the arrangement of their cadherin domains. For example, straightening of the putative bend between EC9 and EC10 of protocadherin 15 could provide a small extension under relevant forces (Figure 1E). Because this flexure is absent in the cryo-electron microscopic class averages presented by Dionne et al. (2018), those authors suggest a different and novel way in which cadherin domains could be rearranged: the helix might unwind under tension, elongating the tip link and contributing compliance to the gating spring (Figure 1F). However, tip links imaged in situ (Kachar et al., 2000) evidently sustain considerable resting tension in the absence of a stimulus. They nonetheless show a helical structure similar to that of the dimeric protocadherin 15 imaged by Dionne et al. (2018) under force-free conditions. This observation suggests that, if the tip link unwinds at all, it does so only under relatively large forces. Additional mechanisms therefore seem necessary to explain the extensibility and stiffness of the gating spring. In particular, a possible entropic contribution to the tip link’s elasticity has largely been ignored. Electron microscopic and crystallographic structures portray the tip link and its constituent proteins as rigid objects that, like macroscopic structures, remain in a given conformation unless exposed to external forces. This impression is misleading. Surrounded by aqueous endolymph, a relaxed tip link is constantly bombarded by water clusters that bend it laterally. Such thermal forces ensure that the link undergoes continuous fluctuations in shape, spending most of its existence with random thermal bends and rarely assuming a straight configuration. To straighten the link by pulling out some of its thermal bends requires the application of an external force; the ensuing work is performed against the link’s entropic elasticity (Figure 1G). Because the mechanical properties of tip-link cadherins are unknown, it is uncertain to what extent entropic elasticity contributes to gating-spring stiffness. An important challenge for future research is to probe the mechanics of tip-link cadherins in single-molecule experiments in order to determine the relative importance of the possible modes of extensibility.
Neuron
Previews ACKNOWLEDGMENTS This work was partially supported by a Junior Fellow award from the Simons Foundation to T.F.B. A.J.H. is an Investigator of Howard Hughes Medical Institute.
Dionne, G., Qiu, X., Rapp, M., Liang, X., Zhao, B., Peng, G., Katsamba, P.S., Ahlsen, G., Rubinstein, R., Potter, C.S., et al. (2018). Mechanotransduction by PCDH15 relies on a novel cis-dimeric architecture. Neuron 99, this issue, 480–492.
REFERENCES
Hudspeth, A.J. (2014). Integrating the active process of hair cells with cochlear function. Nat. Rev. Neurosci. 15, 600–614.
Araya-Secchi, R., Neel, B.L., and Sotomayor, M. (2016). An elastic element in the protocadherin-15 tip link of the inner ear. Nat. Commun. 7, 13458.
Kachar, B., Parakkal, M., Kurc, M., Zhao, Y., and Gillespie, P.G. (2000). High-resolution structure of hair-cell tip links. Proc. Natl. Acad. Sci. USA 97, 13336–13341.
Corey, D.P., and Hudspeth, A.J. (1983). Kinetics of the receptor current in bullfrog saccular hair cells. J. Neurosci. 3, 962–976.
Kozlov, A.S., Andor-Ardo´, D., and Hudspeth, A.J. (2012). Anomalous Brownian motion discloses viscoelasticity in the ear’s mechanoelectrical-
transduction apparatus. Proc. Natl. Acad. Sci. USA 109, 2896–2901. Powers, R.E., Gaudet, R., and Sotomayor, M. (2017). A partial calcium-free linker confers flexibility to inner-ear protocadherin-15. Structure 25, 482–495. Sotomayor, M., Corey, D.P., and Schulten, K. (2005). In search of the hair-cell gating spring: elastic properties of ankyrin and cadherin repeats. Structure 13, 669–682. Sotomayor, M., Weihofen, W.A., Gaudet, R., and Corey, D.P. (2012). Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction. Nature 492, 128–132.
Hippocampal Mossy Cells Provide a Fate Switch for Adult Neural Stem Cells Vero´nica C. Piatti1 and Alejandro F. Schinder1,* 1Laboratorio de Plasticidad Neuronal, Fundacio ´ n Instituto Leloir–Instituto de Investigaciones Bioquı´micas de Buenos Aires–Consejo Nacional
de Investigaciones Cientı´ficas y Te´cnicas (CONICET), Av. Patricias Argentinas 435, Buenos Aires C1405BWE, Argentina *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.07.044
The pathways that convert neural stem cells (NSCs) into functional neurons in the adult hippocampus are tightly regulated. In this issue of Neuron, Yeh et al. (2018) demonstrate that the activity of dentate mossy cells determines the balance between quiescence and activation of NSCs. Neuronal plasticity is the ability of nervous system networks to adjust to the dynamic conditions in the environment. In most circuits, plasticity is expressed as changes in synaptic weight. In a few regions of the adult brain such as the dentate gyrus (DG) of the hippocampus, plasticity also includes neurogenesis: the generation of entire new sets of functional units, the dentate granule cells (GCs). Positive experiences such as enriched environment (EE), voluntary exercise, or spatial learning increase the rate of neurogenesis and accelerate neuronal integration in the existing circuits. In contrast, stress and several pathological conditions reduce this plasticity or render abnormal connectivity of new GCs. Interestingly, not only experience exerts an impact on neurogenesis; new GCs also modify behavior, contributing to cognitive flexibility and
mood regulation (Toda and Gage, 2017). It is thus crucial to understand the mechanisms that control the generation and integration of adult-born GCs. The process starts from quiescent radial neural stem cells (NSCs) that—upon activation—divide, produce amplifying progenitor cells and, finally, produce the daughter cells that may became neuroblasts that will mature and integrate during several weeks into local and long-range dentate circuits (Toda and Gage, 2017). Several steps in the neurogenic pathway from NSCs to the final stages of maturation are modulated in response to mood and cognitive demand. While the parameters that rule these forms of network homeostasis remain largely unknown, it is becoming clear that network activity plays a fundamental role. What cells are the main activity sensors?
The DG is a sparse network in which principal neurons, the GCs, are mostly silent due to a strong GABAergic tone (Piatti et al., 2013). In contrast, mossy cells (MCs), glutamatergic dentate interneurons, are very active and have been proposed as sentinels of the DG network (Scharfman, 2017). Their major inputs arise from GCs, local GABAergic interneurons of the hilus and back-projections from CA3 pyramidal cells. Their output covers a long range of targets. The associational pathway, where axons extend ipsilaterally, covers about 60% of the longitudinal DG axis. The commissural pathway projects to the contralateral DG (Larimer and Strowbridge, 2008; Scharfman, 2017). Therefore, MCs have the capacity to integrate and adjust activity within the DG through excitatory feedback loops connecting GCs and local
Neuron 99, August 8, 2018 ª 2018 Elsevier Inc. 425